title: C-reactive protein promotes acute renal inflammation and fibrosis in unilateral ureteral obstructive nephropathy in mice.
abstract: Elevated blood level of C-reactive protein (CRP) is associated with increased risk of chronic kidney disease. However, whether this association reflects functional importance of CRP in the pathogenesis of kidney disease remains unclear. In this study, we examined the biological role of CRP in a well-characterized model of progressive kidney disease, unilateral ureteral obstruction (UUO), in mice that express the human CRP gene (CRPtg). Compared with wild-type (Wt) mice at 3 days after UUO, CRPtg mice developed more severe renal inflammation with a significant increase in tubulointerstitial T cells and macrophages, upregulation of proinflammatory cytokines (IL-1β and TNF-α), chemokines (MCP-1), and adhesion molecules (ICAM-1). Renal fibrosis was also significantly enhanced in CRPtg mice as demonstrated by increased expression of tubulointerstitial α-smooth muscle actin and collagen types I and III compared with Wt mice. Interestingly, on days 7 and 14 after UUO, an equal severity of renal inflammation and fibrosis were observed in CRPtg and Wt mice. These findings suggested that CRP may have a role in the initiation of renal inflammation and fibrosis. Further study revealed that enhanced early renal inflammation and fibrosis on day 3 in CRPtg mice was associated with a significant upregulation of endogenous mouse CRP and FcγRI mRNA and increased activation of both NF-κB/p65 and TGF-β/Smad2/3 signaling, while equal severity of progressive renal injury at day 7 and day 14 between CRPtg and Wt mice were attributed to equivalent levels of CRP, FcγRI, phospho-NF-κB/p65, and TGF-β/Smad2/3 signaling. Based on these findings, we conclude that CRP may not only be a biomarker, but also a mediator in the early development of renal inflammation and fibrosis in a mouse model of UUO. Enhanced activation of both NF-κB and TGF-β/Smad signaling pathways may be mechanisms by which CRP promotes early renal inflammation and fibrosis.
authors.affiliation: Department of Medicine-Nephrology, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Z I
authors.initials: ZI
authors.lastname: Li
authors.forename: Arthur C K
authors.initials: AC
authors.lastname: Chung
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.forename: J M
authors.initials: JM
authors.lastname: Fan
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D014517:Ureteral Obstruction / Q000378:metabolism*
chemical_list: D000199:Actins; D015815:Cell Adhesion Molecules; D018925:Chemokines; D024042:Collagen Type I; D024043:Collagen Type II; D016207:Cytokines; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D002097:C-Reactive Protein